A large but inconclusive body of evidence implicates the role of biogenic amines in the biology of depression and in the mechanism of action of antidepressant drugs. Neurochemical and pharmacological data derived from acute drug effects constitute the bulk of evidence. However, in clinical practice, the efficacy of these agents is slow in developing and requires prolonged periods of treatment. This consideration focuses on the relevance of the study of chronic effects of antidepressants. We propose to study the effects of long-term administration of MAO inhibitors, tricyclic antidepressants, chlorpromazine and some antihistamines that have been shown to have antidepressant potential on the basis of preclinical pharmacology. The effect of these drugs on the synthesis, uptake, release and catabolism of the biogenic amines (norepinephrine, dopamine, serotonin and acetylcholine) and the enzymes involved in their syntheses and catabolism will be investigated. Experiments designed to extend our previous data on serotonin receptor supersensitivity and aimed at exploring the effect of chronic antidepressant medication on pre- and post-synaptic receptors will also be undertaken. Receptor function will be assessed by binding studies, cyclase measurements and functional-behavioral measurements. This evaluation of neurochemical and pharmacological effects of long-term administration of these psychoactive agents will aid in (1) finding a unifying concept for the antidepressant action of these agents, (2) postulating on the underlying defect in pathological Depression, and (3) improving the basis of prediction of clinical activity of antidepressant drugs.